Despite the explosive increase in cocaine abuse, little information is available with respect to the effects, in human brain, of long-term exposure to this drug. The major objective of our study is to conduct, for the first time, a systematic and comprehensive examination of the behaviour of the major neurotransmitter systems in autopsied brain of cocaine abusers. We propose to test the Specific Hypothesis that chronic cocaine abuse will be associated with long-lasting depletion in autopsied human brain in the markers for the monoamine neurotransmitters as assessed by HPLC, quantitative autoradiography, receptor binding, and photoaffinity labelling procedures. Autopsied cocaine-abused brain (n=10 per year for the next three years) will be carefully selected from over 250 possible autopsies at one Canadian (Toronto) and two U.S. (Minneapolis; Bronx, N.Y.) centers. The obtained neurochemical data will be compared with biochemical findings obtained in two drug (chronic heroin; alcohol) and one non-neurological group. All of the applicants have demonstrated expertise in the relevant human brain dissection, neurochemical, and neuropathological components of this investigation. Much effort is now being directed to experimental animal studies designed to understand the biochemical basis of cocaine addiction and the long-term changes in brain following chronic cocaine abuse. We argue that such studies should more appropriately be conducted in the human brain. We suggest that the results of our intensive study will provide, for the first time, baseline information with respect to the potential long-term pharmacologic/neurotoxicological efforts of cocaine as well as a springboard for formulating new treatment strategies for the human cocaine abuser.